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The association between tic medication therapy and psychiatric comorbidities among patients with Tourette syndrome: A national population-based study in Taiwan
Brain & Development 42 (2020) 373–382 www.elsevier.com/locate/braindev
Original article
The association between tic medication therapy and psychiatric comorbidities among patients with Tourette syndrome: A national population-based study in Taiwan Chia-Wen Chen a, Chang-Wei Hsueh b, Chi-Hsiang Chung c, Huei-Shyong Wang d Hsiu-Ju Chang a,⇑,1, Wu-Chien Chien c,⇑,1 a
School of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan b Division of Pediatric Neurology, Landseed Hospital, Taoyuan, Taiwan c School of Public Health, National Defense Medical Center, Taiwanese Injury, Taipei, Taiwan d Division of Pediatric Neurology, Chang Gung Children’s Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan Received 13 December 2018; received in revised form 8 January 2020; accepted 9 January 2020
Abstract Background: Tourette syndrome (TS) is often comorbid with attention deficit hyperactivity disorder, obsessive–compulsive disorder, and depression. Medications are the main treatment for TS. Relationships between TS medication therapy and psychiatric comorbidities remain unclear. This study explored the impacts of TS medication on the risk of psychiatric comorbidities using a nationally representative sample of TS in Taiwan. Methods: Data from National Health Insurance Research Database in Taiwan was used to identify 997,213 children and adolescents aged 6–18 years who had received a diagnosis of TS based on ICD-9-CM codes in 2000–2010. Cox’s proportional hazard regression analysis was conducted to estimate the risk of comorbidities among subjects with and without tic medication therapy. Results: We found that in TS patients, a lower risk of psychiatric comorbidities occurred in the tic medication therapy group (p = 0.012) and the crude hazard ratio (HR) was 0.6 (95% confidence interval (CI) = 0.4–0.8, p < 0.001). After adjusting for potential confounders of gender, age, income, level of care, department visited, brain injury, and the number of suicide attempts, the risk of comorbidities was still significantly lower in the tic medication therapy group (adjusted HR = 0.5, 95% CI = 0.3–0.6, p < 0.001). Discussion: One limitation was that we did not include all mediations used to treat psychiatric comorbidities among TS patients. This study found the effectiveness of TS medications on improving psychiatric comorbidities. Conclusions: Compared to those without medication, medication therapy appears to have a benefit of decreasing the risk of psychiatric comorbidities. Strategies to improve medication regimens should be considered in clinical settings. Ó 2020 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Keywords: Tourette syndrome (TS); Medication therapy; Psychiatric comorbidity; Treatment outcome; Research database
1. Introduction ⇑ Corresponding authors.
E-mail addresses: [email protected] (H.-J. Chang), chienwu@ mail.ndmctsgh.edu.tw (W.-C. Chien). 1 Contributed equally.
Tourette Syndrome (TS) (also called Tourette disorder) is a chronic neurologic disorder defined by multiple motor tics and at least one phonic tic that persist for at least a year, generally emerging between the ages of 5
https://doi.org/10.1016/j.braindev.2020.01.002 0387-7604/Ó 2020 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
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and 8 years, with tic severity generally peaking between the ages of 10 and 12 years [1]. Chronic tic disorder (CTD) is defined by the presence of either motor or vocal tics and is less frequently associated with cooccurring neuropsychiatric conditions, such as attention deficit hyperactivity disorder (ADHD) and obsessive– compulsive disorder (OCD) [2]. Severe cases TS and CTD can lead to significant physical and psychosocial morbidity [2]. The onset of the tic symptoms of TS in Taiwan usually occurs before the tenth birthday in 84% of cases [3]. Based on a nationally representative sample in 2011–2012, 0.19% children in the USA aged 6–17 years currently had TS, representing 73% of children ever diagnosed with TS [1]. The prevalence of TS in childhood of 6 per 1000 was replicated in several countries [4–6]. Recent studies also showed that the ratio of males to females with TS aged 4–6 years was approximately 4:1 [7]. In Taiwan, the ratio of male to female was 9–2 and the comorbid rate of ADHD 36%, OCD was 18%, and self-injurious was 27% [8]. The onset of tic symptoms in TS typically occurs during early childhood, and the disorder affects 0.15–3.8% of Western and 0.56% of Taiwanese school-aged children [8– 11]. Children currently with TS are three times as likely as children without TS to have ever had any cooccurring neurobehavioral conditions; 86.5% of children currently with TS had at least one co-occurring neurobehavioral condition [1]. Almost 90% of all children diagnosed with TS exhibit symptoms of one or more comorbid disorders [11]. Among those children with TS, more than half of them show evidence of psychiatric comorbidities, including ADHD, OCD, mood disorders, and behavioral problems [11–13]. Approximately 10% of all children with TS experience mood disorders such as depression [7]. One study found that TS patients were 4.6 times more likely to develop depression than were patients without TS [10]. Similarly, some studies showed that only 12% patients with TS presented with no other coexisting disorders [2,14]. Comorbidity rates associated with TS were 30–50% for ADHD, 25–42% for OCD, and 27% for self-injurious behaviors [15,16]. A recent study also showed that patients with TS have a high risk of developing depression, and males were more likely to be diagnosed with depression than females in Taiwan [11]. In addition, children diagnosed with TS were 2.6-times more likely to have had a brain injury or concussion, and a lower socioeconomic status was also associated with a twofold increase in the risk of TS [1,17]. Instead of removing the tics, the treatment goal for children with TS is maximizing their potential in school settings and social functioning by targeting the following conditions that result from tics [18]: (1) subjective discomfort (e.g., pain or injury); (2) sustained social problems (e.g., social isolation or bullying); (3) social
and emotional problems (e.g., reactive depressive symptoms); and (4) functional interference (e.g., impairment of academic achievements). According to Kurlan [16] clinical guidelines for treating TS and other tic disorders primarily rely on medications, such as alpha agonists (e.g., clonidine and guanfacine), antipsychotics (e.g., haloperidol, fluphenazine, pimozide, and risperidone), and dopamine receptor antagonists (e.g., tetrabenazine). Several trials supported the efficacy of the alpha adrenergic drugs, clonidine and guanfacine, as first-line therapy for TS [16,19]. European clinical guidelines for TS and other tic disorders state that the typical antipsychotics, haloperidol and pimozide, are the most effective medications for tic management [20,21]. Also, a study by Kurlan [16] suggested that the only FDA-approved medications for TS are classical neuroleptic antipsychotic drugs, such as haloperidol and pimozide. These medications work by blocking the production of D2 dopamine receptors antagonist in the brain, which results in suppression of the tics [16]. The most common side effects of these antipsychotic medications are sedation and depression [16]. In addition, alpha agonist medications (e.g., clonidine and guanfacine) are used as firstline therapy for TS and tics, and the effectiveness of treating ADHD children with comorbid TS was evaluated in double-blind, placebo-controlled studies [19,21,22]. In Taiwan, medications commonly used for TS include a2-adrenergic agonists and atypical antipsychotics [23–25]. Effective a2-adrenergic agonists include clonidine. Atypical antipsychotics are the most effective drugs for treating tics because they show reduced incidence of side effects. Examples include aripiprazole, ziprasidone, sulpiride, olanzapine, quetiapine, risperidone, and clozapine. To date, aripiprazole appears to display a novel neuroleptic effect that has been demonstrated to be effective in treating TS children in several studies in Taiwan [23,24,26]. In addition, guanfacine is not used in Taiwan. Recent epidemiologic studies demonstrated that TS is more common than previously recognized. However, previous studies examining the impact of TS have been limited generalizability to larger populations, and behavioral interventions have not been evaluated in large-scale controlled trails. Early treatment of TS involves pharmacologic and/or behavioral interventions [11,16]. Atypical antipsychotics should be the main component of any treatment plan for tics and TS, to aid in treating comorbid disorders such as depression, anxiety, OCD, and ADHD [21]. Nevertheless, relatively little is known about a holistic view of the impacts of tic medication for TS on psychiatric comorbidities while controlling for relevant factors in Taiwan. Also, there is a need for a study with a large sample size and long-term outcomes of medications for TS. The aim of this study was therefore to explore the
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impacts of tic medication on the risk of psychiatric comorbidities among a nationally representative sample of children and adolescents with TS based on the Taiwan National Health Insurance (NHI) Research Database (NHIRD). 2. Methods 2.1. Study design and data source This study uses a retrospective cohort design. Data used for this analysis were from an NHI database. Taiwan implemented its NHI on March 1, 1995, and the health insurance coverage rate currently exceeds 99%. The NHI was launched in Taiwan to provide equal access to adequate health care for all and to provide medicated interventions faster and as needed [27]. The NHI database includes nationwide outpatient/ emergency and hospitalization data, and the law requires that all hospitals and clinics report outpatient/ emergency and hospitalization expenses to the Bureau of NHI on a monthly basis. This study used the Longitudinal Health Insurance Database (LHID), which contains all original claims data of one million beneficiaries, randomly sampled from the registry for Beneficiaries of the NHIRD with more than 23 million individuals enrolled in the NHI program, the universal single-payer for healthcare in Taiwan. The diagnostic codes used in the NHIRD follow the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). Each TS diagnosis was made by a board-certified pediatrician or neurologist according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). The NHI Administration randomly chose the records of 1 in 100 ambulatory care visits and 1 in 20 inpatient claims to verify the accuracy of the diagnoses. Several studies have demonstrated [9] high accuracy and validity of the diagnoses in the NHIRD [27]. Therefore, using the NHIRD is suitable to explore the effects of tic medication on the risk of psychiatric comorbidities in new diagnoses of TS. 2.2. Variable definitions In our research, TS were identified by the ICD-9CM codes of 307.22 and 307.23, which include both outpatient and inpatient participants. Three most common comorbidity event for tracking included ADHD (ICD-9-CM 314), OCD (ICD-9-CM 300.3), and depression (ICD-9-CM 296.20–296.26, 296.30–296.36, 300.4, 311) [10,16]. Medication therapy for TS included alpha-agonists, antipsychotics, and dopamine receptor antagonists [16]. Patients were considered to have low income based on certifications of waived medical copayments.
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2.3. Study sample In Taiwan, TS is diagnosed by health professionals according to DSM-5 to help diagnose tic disorders [28]. To be diagnosed with TS, a person must first have two or more motor tics (for example, blinking or shrugging the shoulders) and at least one vocal tic (for example, humming, clearing the throat, or yelling out a word or phrase), although they might not always happen at the same time. Second, the tics have to have persisted for at least a year. The tics can occur many times a day (usually in bouts) nearly every day, or on and off. Third, the tics must have begun before the age of 18 years. Lastly, the symptoms must not be due to medication or other drugs or to any other medical condition (for example, seizures, Huntington disease, or postviral encephalitis). Individuals aged 6–18 years who had sought medical help from outpatient, emergent, and inpatient departments due to TS were identified as potential subjects for this study. Initially, 935 individuals among 997,213 persons were aged 6–18 years and had been diagnosed with TS from January 1, 2000 to December 31, 2010. The specific inclusion criteria for this study were those newly diagnosed with TS from January 1, 2000 to December 31, 2010. The establishment of the health insurance database began in 1995, but it was not fully guaranteed in the first few years of operation, and the quality of the data in previous years was insufficient. The data improved in 1997, so we purchased the database from 1997 and excluded outpatients or inpatients seen for TS in the period of 1997–1999. We excluded outpatients or inpatients due to TS in 1997–1999 to ensure that the selected cases were new ones in 2000. In addition, new cases of TS who had a past history of ADHD, OCD, or depression in 1997–1999 were also excluded to ensure that the traced comorbidities were not due to the past psychiatric history. Subjects with an unknown gender were also excluded, and the tracking time was 1–11 years. Twelve subjects met the above exclusion criteria. Ultimately, the study sample consisted of 921 individuals; we then divided them into two groups of ‘‘with tic medication therapy (589 individuals)” and ‘‘no tic medication therapy (332 individuals).” Subjects were tracked until December 31, 2010 (Fig. 1). In addition, the patient records were collected from January 1, 2000, to December 31, 2010, and the follow up deadline was until December 31, 2010. After inclusion, the comorbidities of participants with TS were traced. We first included patients with medication and then traced their comorbidities during the follow-up period. The years of follow up between medication groups with and without tics were 3.54 years and 3.06 years, respectively. We calculated the total follow up time until comorbid events for the medication group with tics,
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Fig. 1. Flowchart of study sample selection from the National Health Insurance Research Database in Taiwan. ADHD, attention deficit hyperactivity disorder; OCD, obsessive–compulsive disorder.
which included 589 individuals, from 2000 to 2010. We then determined the mean follow-up time, which was 2.67 years. The same calculation was applied to the medication group without tics, and the follow-up time until comorbid events was 2.11 years.
medication therapy on psychiatric comorbidities. To investigate the interaction effects, we also calculated adjusted HRs stratified by gender and age groups. All statistical analyses were performed with SPSS 22.0 software (SPSS, Chicago, IL, USA), and two-tailed p < 0.05 was considered the threshold for a significant variance.
2.4. Statistical analysis 2.5. Ethical considerations We used Chi-squared/Fisher exact tests and t-tests to compare differences between groups with and without tic medication therapy and from the baseline to the tracking endpoint. A Kaplan-Meier curve and Cox’s proportional hazard regression analysis were performed to calculate the crude and adjusted hazard ratios (HRs), with the 95% confidence interval (CI), for the effect of tic
NHI information offers representative empirical data for medical and health-related research fields. Researchers are required to pass a detailed review by a professional peer review committee before they are allowed to use the Taiwan NHIRD. Because participants’ identities are encrypted in the database, this study did not
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infringe on participants’ right to privacy. Our study had been approved by the hospital IRB committee (Protocol No.16-026-B1). 3. Results 3.1. Characteristics of study subjects As shown in Table 1, the study included a final cohort of 921 participants with Tourette syndrome, comprising 589 patients in the tic medication therapy group and 332 patients in the no tic medication therapy group. The mean age of patients in the tic medication therapy group was younger than in the no tic medication therapy group (9.12 vs. 9.75 years, p < 0.001). Our study revealed that the incidence of TS in Taiwan is about 0.09%, and the prevalence is 0.54%. Regardless of whether TS patients were examined as a group or were divided into different age groups, male patients were more common than female patients. However, this difference did not reach statistical significance. At the end of follow-up, 94 participants in the tic medication therapy group had had a comorbid event, and 90 participants in the no tic medication therapy group had had an event. Compared to the no tic medication therapy group, the medication therapy group had a lower risk of the occurrence of a comorbidity (p < 0.001). Specifically, patients in the medication therapy group had a lower comorbidity proportion of ADHD (p < 0.001), whereas the comorbidity occurrences of OCD and depression did not significantly differ between the tic medication therapy and no tic medication therapy groups (Table 1). There were no significant differences between with and no tic medication therapy groups regarding income, level of care, department visited, brain injury, or number of suicide attempts. The study found that the percentage of comorbidity events during the study period in 2001 was 12.5% through 2008, when it was 23.86%; it then decreased to 17.05% in 2010. Also, the percentage of comorbidity events in males was higher than that in females of 6–18 years of age. 3.2. The effect of tic medication therapy As to the effect of tic medication therapy on psychiatric comorbidities, Cox’s proportional hazard regression analysis showed a statistically significant reduction in ADHD, OCD, and depression in the tic medication therapy group with a crude HR of 0.6 (95% CI = 0.4–0.8, p < 0.001) (Table 2). After controlling for gender, age, income, level of care, department visited, brain injury, and the number of suicide attempts, the risk of psychiatric comorbidities was still significantly lower in the tic medication therapy group (adjusted HR = 0.5, 95% CI = 0.3–0.6, p < 0.001)
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(Table 2). The Kaplan-Meier curve showed a lower risk of psychiatric comorbidities in the tic medication therapy group after controlling for gender, age, income, level of care, department visited, brain injury, and the number of suicide attempts (p = 0.012) (Fig. 2). The event rate of psychiatric comorbidities was 46.60 per 1000 person-years in the tic medication therapy group, and it was 86.90 per 1000 person-years in the no tic medication therapy group. In addition, we conducted an advanced analysis by stratifying by gender and age groups, and results showed a lower risk of event occurrence in the tic medication therapy group in both genders and all age groups after adjusting for income, level of care, department visited, brain injury, and the number of suicide attempts. In other words, regardless of the gender or age group, the effect of tic medication therapy on reducing the risk of psychiatric comorbidities was still significant (Table 3). 4. Discussion The major aim of this study was to explore the impacts of TS medications on the risk of psychiatric comorbidities among a nationally representative sample of children and adolescents with TS using data from the NHIRD in Taiwan. Consistent with a previous study [16], our study found that regardless of TS patients in total or divided into different age groups, male patients were more common than female patients. Compared to the no tic medication therapy group, patients in the medication therapy group had a lower risk of psychiatric comorbidities at the end of follow-up (p < 0.001). Specifically, patients in the medication therapy group had a lower risk of ADHD (p < 0.001), whereas the comorbidities of OCD and depression did not significantly differ between the tic medication therapy and no tic medication therapy groups. After adjusting for gender, age, income, level of care, department visited, brain injury, and the number of suicide attempts, results showed that TS patients with tic medication therapy tended to have fewer occurrences of ADHD, OCD, and depression than those without tic medication therapy (adjusted HR = 0.5, 95% CI = 0.3–0.6, p < 0.001). Further analysis showed that the effect of tic medication therapy was still significant regardless of gender or age group. The most often used medications for TS during the past 10 years included alpha agonists (e.g., clonidine and guanfacine), antipsychotics (e.g., haloperidol, risperidone, fluphenazine, pimozide, aripiprazole, ziprasidone, sulpiride, olanzapine, quetiapine, and clozapine), and dopamine receptor antagonists (e.g., tetrabenazine) [38]. Few studies have examined the effects of medication therapy on improving psychiatric comorbidities. Several trials supported the efficacy of pharmacological therapy (most commonly alpha ago-
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Table 1 Characteristics of the study sample at the baseline. Variable
Total (N = 921) n (%)
Without tic medicine (N = 332) n (%)
With tic medicine (N = 589) n (%)
p
Age, years (mean ± SD)
9.5 ± 2.6
9.8 ± 2.7
9.12 ± 2.3
<0.001
Age groups, years 6–12 years 13–15 years 16–18 years
829 (90.0) 70 (7.6) 22 (2.4)
312 (94.0) 16 (4.8) 4 (1.2)
517 (87.8) 54 (9.2) 18 (3.1)
Gender Male Female
741 (80.5) 180 (19.5)
268 (80.7) 64 (19.3)
473 (80.3) 116 (19.7)
Age group: 6–12 years Male Female
672 (81.1) 157 (18.9)
255 (81.7) 57 (18.3)
417 (80.7) 100 (19.3)
Age group: 13–15 years Male Female
51 (72.9) 19 (27.1)
9 (56.3) 7 (43.8)
42 (77.8) 12 (22.2)
Age group: 16–18 years Male Female
18 (81.8) 4 (18.2)
4 (100) 0 (0)
14 (77.8) 4 (22.2)
Comorbid events With Without
184 (20.0) 737 (80.0)
90 (27.1) 242 (72.9)
94 (16.0) 495 (84.0)
ADHD With Without
156 (16.9) 765 (83.1)
83 (25) 249 (75)
73 (12.4) 516 (87.6)
OCD With Without
15 (1.6) 906 (98.4)
4 (1.2) 328 (98.8)
11 (1.9) 578 (98.1)
Depression With Without
21 (2.3) 900 (97.7)
5 (1.5) 327 (98.5)
16 (2.7) 573 (97.3)
Level of income Low High
16 (1.7) 905 (98.3)
4 (1.2) 328 (98.8)
12 (2.0) 577 (98.0)
Level of care Medical hospital Regional hospital Local hospital Physician clinic
150 (16.7) 137 (15.2) 22 (2.4) 592 (65.7)
43 (13.0) 46 (13.9) 17 (5.1) 226 (68.1)
107 (18.8) 91 (16.0) 5 (0.9) 366 (64.3)
Department visited Pediatrics Psychiatry Others
607 (65.9) 206 (22.4) 108 (11.7)
218 (65.7) 75 (22.6) 39 (11.8)
389 (66.0) 131 (22.2) 69 (11.7)
Brain Injury With Without
0 (0) 921 (100)
0 (0) 332 (100)
0 (0) 589 (100)
No. of suicide attempts 0 1
921 (100) 0 (0)
332 (100) 0 (0)
589 (100) 0 (0)
0.475
0.387
0.086
0.418
<0.001
<0.001
0.319
0.171
0.258
0.143
0.992
–
–
nists and antipsychotics) for TS. Alpha-2 adrenergic drugs, including clonidine and guanfacine, are also efficacious for ADHD [19,20]. Indeed, alpha agonists may be a good first-line treatment in patients with both tics
and ADHD [16]. Atypical antipsychotics should be an option for tics and TS to aid in treating comorbid disorders such as depression, anxiety, OCD, and ADHD [2,3,19].
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Table 2 Factors of comorbid events (attention deficit hyperactivity disorder/obsessive–compulsive disorder/depression) at the end of follow-up using a Cox regression. Variable
Crude HR (95% CI)
p
Adjusted HR (95% CI)
p
Tic medicine therapy With Without
0.6 (0.4–0.8) Reference
<0.001
0.5 (0.3–0.6) Reference
<0.001
Gender Male Female
2.1 (1.3–3.3) Reference
<0.001
1.2 (0.7–2.0) Reference
0.469
Starting age group (years) 6–12 13–15 16–18
Reference 1.6 (1.0–2.6) 2.0 (1.0–4.1)
Level of income Low High
0.7 (0.2–2.6) Reference
0.54
0.3 (0.1–1.3) Reference
0.10
Level of care Medical hospital Regional hospital Local hospital Physician clinics
17.1 (11.02–26.42) 14.0 (9.0–21.9) 8.3 (4.2–16.4) Reference
<0.001 <0.001 <0.001
15.3 (9.7–24.0) 11.3 (7.1–17.9) 8.7 (4.4–17.2) Reference
<0.001 <0.001 <0.001
Department visited Pediatrics Psychiatry Others
0.72 (0.1–5.1) 5.73 (4.3–7.7) Reference
0.74 <0.001
1.3 (0.2–9.5) 3.36 (2.5–4.6) Reference
0.79 <0.001
0.048 0.052
Reference 1.3 (0.8–2.1) 1.2 (0.6–2.5)
0.258 0.619
HR, hazard ratio; CI, confidence interval.
Fig. 2. Kaplan-Meier curve for cumulative survive of events (attention deficit hyperactivity disorder (ADHD)/obsessive–compulsive disorder (OCD)/depression) stratified by tic medicine therapy according to the log-rank test.
However, atypical antipsychotics are often associated with adverse effects [21]. It was recommended that OCD is genetically associated with TS [2,3,19]. OCD symptoms are significantly related to core symptoms of TS [23]. One study also found that patients with TS
reported similar scores as those patients with major depressive disorder on obsessionality, indicating that obsessionality commonly occurs in TS [30]. TS comorbid with OCD is associated with more-severe tics, echophenomena, ADHD, and depression [31]. The effec-
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Table 3 Factors of comorbid events (attention deficit hyperactivity disorder/obsessive–compulsive disorder/depression) at the end of follow-up stratified by gender and age group using a Cox regression. py
With tic medicine (N = 589)
Without tic medicine (N = 332) (Reference)
Adjusted HR (95% CI)
p
86.9
0.458 (0.3–0.6)
<0.001
799 236.68
103.9 29.6
0.43 (0.3–0.6) 0.6 (0.2–0.8)
<0.001 <0.01
978.3 50.97 6.38
84.8 78.5 470.2
0.4 (0.3–0.6) 0.7 (0.1–0.8) 0.4 (0.1–0.7)
<0.001 <0.01 <0.01
Comorbid events
PYs
Rate (per 103)
Comorbid events
PYs
Rate (per 103)
Total
94
2017.29
46.6
90
1035.7
Gender Male Female
81 13
1527.06 490.23
53 26.5
83 7
1697.66 287.8 31.83
43 55.6 157.1
83 4 3
Age group (years) 6–12 73 13–15 16 16–18 5
PYs, person-years; HR, hazard ratio; CI, confidence interval.
tiveness of medication therapy in improving psychiatric comorbidities may be explained by a common neuropsychiatric mechanism among TS, ADHD, OCD, and depression. For example, it was recommended that because of complicated interactions between dopamine and serotonin in the brain, it is possible that both systems play a role in both TS and OCD, suggesting that medications which are effective in OCD (such as serotonin reuptake inhibitors (SRIs), may also be useful for treating TS [32]. In Taiwan, two classes of medicine are widely used for TS: a2-adrenergic agonists and atypical antipsychotics [23,25]. Clonidine is usually the first-line medication for previously untreated TS patients. Aripiprazole appears to display a novel neuroleptic effect that has been demonstrated to be effective in treating TS children in several studies [23,25,26]. In 2016, the Ministry of Health and Welfare also approved the use of aripiprazole to treat dysentery, and it is also the first choice in Taiwan [24,25]. TS has been shown to have a prevalence of about 6 per 1000 among childhood in several countries [4–6]. The onset of tic symptoms in TS typically occurs during early childhood, and the disorder affects 0.15–3.8% of children in Western countries [9]. Wang did an epidemiological study in an elementary school with 2000 Taiwanese children with TS, which had a prevalence of about 0.56% [8]. Our study also found a similar prevalence of TS for children aged 6 to 18 years of around 0.54%. However, the prevalence in Taiwan is lower than in Western countries. This might be due to the insufficient awareness about TS in Taiwan, where many pediatric patients do not receive early diagnosis and are mistreated or punished because of their disorderrelated behaviors. Our study found that the percentage of comorbidity events during the study period was lower than in other studies. For example, one Canadian study examined 65 individuals with TS identified in childhood and 65 matched community controls without tics or OCD symptoms. The participants were assessed around
18 years of age in regard to psychosocial functioning and lifetime psychiatric disorders. It was found that approximately 40% of children with TS had experienced depression or OCD [33]. In a Swedish study of 4479 school-aged children, 25 had TS, 34 had chronic motor tics (CMT), 24 had chronic vocal tics (CVT), and 214 had transient tics (TT) during the past year. A three-stage procedure was used, which involved tic screening, telephone interviews, and clinical assessment. The TS group was compared with 25 children with TT and 25 controls without tics. The study found that 66% of the TS cases had comorbid ADHD, and 54% of the children with TS had comorbid OCD [34]. The inconsistency with our findings might be because our study used existing diagnoses that were available in a dataset without clinical assessment or diagnosis tools like those used in other studies to confirm the diagnosis, which might have resulted in underestimation of the occurrence of psychiatric comorbidities. In line with previous studies, our study found that ADHD was the most common comorbid disorder. Previous studies found that rates of ADHD comorbidity were 38% and 60% in community and referral centers, respectively. ADHD usually occurs approximately 2– 3 years before tics, and a smaller proportion of ADHD patients are found only after tics [35]. Studies suggested that patients with TS and ADHD demonstrated more maladaptive behaviors and showed negative impacts on psychosocial outcomes [29]. Regardless of clinical or community populations, approximately 90% of patients with TS had comorbidities of other psychiatric diagnoses [36]. One study in Japan found that TS patients with comorbidities of OCS and/or hyperkinetic disorder (HD) demonstrated significantly more coprophenomena, higher prevalence rates of impulsiveness/aggression (48.8% vs. 8.3%), school refusal (34.1% vs. 14.3%), self-injurious behaviors (19.0% vs. 2.8%), and clumsiness (23.3% vs. 2.9%) than did the TS-only group [37]. Compared to the TS only or control group, youngsters with TS and ADHD
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showed more internalized behavioral problems and poorer social adaptation [36]. Therefore, it is suggested that all pediatric patients with tics should be screened for an ADHD diagnosis when seeking medical attention [38] and this apparently implies that further management and prognoses may be required [36]. We found that among a final cohort of 921 participants with TS, 332 (36.05%) patients were in the no tic medication therapy group. Treatment of tics needs to be individually tailored, especially when other comorbid disorders occur and affect the clinical course [39]. It is recommended that pharmacological treatment is not always required. Situations can be used to judge which medications have the most troublesome signs (motor component, urge, ADHD, OCD), and interfere with daily living, school, and social functioning [40]. Indeed, it is laborious to provide guidelines about indications for the pharmacological treatment of TS. First, a high interindividual variability of symptoms is shown in patients with TS. Furthermore, there are temporal variations in tics, and the treatment effects for the tics may be affected by coexisting conditions. Furthermore, subjective impairment and objective tic severity are not necessarily correlated with each other. In some cases, people with severe tics show mild impairment, whereas in other cases, mild tics may be associated with significant suffering [18,41]. Although our study found that TS medication was effective in improving the risk of psychiatric comorbidities, the treatment of TS still needs to involve appropriate psychoeducation, behavioral interventions (such as a comprehensive behavioral intervention for tics (CBIT), and social support [16]. In addition to individual considerations for pharmacological treatment, TS medications are often associated with adverse effects, which further result in patients discontinuing their medication. One study [42] reported that 66.7% of patients had discontinued haloperidol due to its intolerable side effects. Although aripiprazole is considered to have fewer adverse effects compared to other atypical antipsychotics, one study still found that 20.7% of patients discontinued its use because of the severity of side effects such as sedation and sleep problems [43]. In Taiwan, caregivers of patients with TS might be concerned about the side effects of medication and refuse to accept pharmacological treatment for those patients. On the other hand, TS patients might also refuse to continue to take a medication because of interruptions to school life due to intolerable adverse drug reactions. 5. Limitations This study has three limitations. First, this study excluded people who were older than 18 years, those who were healthy and did not have health insurance,
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and those who were not covered by NHI program in Taiwan. Second, this study may have been vulnerable to a possible urban–rural imbalance in awareness of mental disorders and access to clinical services. Finally, this study used a claims dataset with scrambled patient identification in order to protect patient’s privacy; therefore, it lacked detailed patient information, such as symptom severity, physical activity of patients, socioeconomic status, and family history of systemic or neuropsychiatric diseases, which may be potential risk factors and confounders related to psychiatric comorbidities. Even though Taiwan’s NHI administration randomly examines cases in order to ensure the accuracy of its database, evidence from a cohort study is usually less reliable than random trials, since a cohort study design is subjected to many biases related to confounder adjustments. We suggest that a future study should be conducted using both qualitative interviews and questionnaire surveys to compare results obtained in this study. 6. Conclusions The studies of TS have been very limited in Taiwan, in particular, relationships between tic medication therapy and psychiatric comorbidities of children and adolescents remain unclear. This study provides the first nationwide, population-based study of children and adolescents with TS in Taiwan which explored the impacts of TS medication on the risk of psychiatric comorbidities. Results revealed that the risk of the occurrence of comorbidities was significantly lower in the tic medication therapy group and also provide evidence to inform the prognoses of patients with TS. These findings imply the importance of early identification and pharmacological treatment which might be helpful in decreasing psychiatric comorbidities. Further studies are still needed to compare and explore the effects of pharmacological and psychosocial treatments.
Acknowledgements This study was supported by the Tri-Service General Hospital Research Foundation (TSGH-B-109010), and the sponsor has no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. References [1] Bitsko RH, Holbrook JR, Visser SN, Mink JW, Zinner SH, Ghandour RM, et al. A national profile of Tourette syndrome, 2011–2012. J Dev Behav Pediatr 2014;35:317–22. [2] Scharf JM, Miller LL, Mathews CA, Ben-Shlomo Y. Prevalence of Tourette syndrome and chronic in the population-based Avon longitudinal study of parents and children Cohort. J Am Acad Child Adolesc Psychiatry 2012;51:192–201.
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Original article
The association between tic medication therapy and psychiatric comorbidities among patients with Tourette syndrome: A national population-based study in Taiwan Chia-Wen Chen a, Chang-Wei Hsueh b, Chi-Hsiang Chung c, Huei-Shyong Wang d Hsiu-Ju Chang a,⇑,1, Wu-Chien Chien c,⇑,1 a
School of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan b Division of Pediatric Neurology, Landseed Hospital, Taoyuan, Taiwan c School of Public Health, National Defense Medical Center, Taiwanese Injury, Taipei, Taiwan d Division of Pediatric Neurology, Chang Gung Children’s Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan Received 13 December 2018; received in revised form 8 January 2020; accepted 9 January 2020
Abstract Background: Tourette syndrome (TS) is often comorbid with attention deficit hyperactivity disorder, obsessive–compulsive disorder, and depression. Medications are the main treatment for TS. Relationships between TS medication therapy and psychiatric comorbidities remain unclear. This study explored the impacts of TS medication on the risk of psychiatric comorbidities using a nationally representative sample of TS in Taiwan. Methods: Data from National Health Insurance Research Database in Taiwan was used to identify 997,213 children and adolescents aged 6–18 years who had received a diagnosis of TS based on ICD-9-CM codes in 2000–2010. Cox’s proportional hazard regression analysis was conducted to estimate the risk of comorbidities among subjects with and without tic medication therapy. Results: We found that in TS patients, a lower risk of psychiatric comorbidities occurred in the tic medication therapy group (p = 0.012) and the crude hazard ratio (HR) was 0.6 (95% confidence interval (CI) = 0.4–0.8, p < 0.001). After adjusting for potential confounders of gender, age, income, level of care, department visited, brain injury, and the number of suicide attempts, the risk of comorbidities was still significantly lower in the tic medication therapy group (adjusted HR = 0.5, 95% CI = 0.3–0.6, p < 0.001). Discussion: One limitation was that we did not include all mediations used to treat psychiatric comorbidities among TS patients. This study found the effectiveness of TS medications on improving psychiatric comorbidities. Conclusions: Compared to those without medication, medication therapy appears to have a benefit of decreasing the risk of psychiatric comorbidities. Strategies to improve medication regimens should be considered in clinical settings. Ó 2020 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Keywords: Tourette syndrome (TS); Medication therapy; Psychiatric comorbidity; Treatment outcome; Research database
1. Introduction ⇑ Corresponding authors.
E-mail addresses: [email protected] (H.-J. Chang), chienwu@ mail.ndmctsgh.edu.tw (W.-C. Chien). 1 Contributed equally.
Tourette Syndrome (TS) (also called Tourette disorder) is a chronic neurologic disorder defined by multiple motor tics and at least one phonic tic that persist for at least a year, generally emerging between the ages of 5
https://doi.org/10.1016/j.braindev.2020.01.002 0387-7604/Ó 2020 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
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and 8 years, with tic severity generally peaking between the ages of 10 and 12 years [1]. Chronic tic disorder (CTD) is defined by the presence of either motor or vocal tics and is less frequently associated with cooccurring neuropsychiatric conditions, such as attention deficit hyperactivity disorder (ADHD) and obsessive– compulsive disorder (OCD) [2]. Severe cases TS and CTD can lead to significant physical and psychosocial morbidity [2]. The onset of the tic symptoms of TS in Taiwan usually occurs before the tenth birthday in 84% of cases [3]. Based on a nationally representative sample in 2011–2012, 0.19% children in the USA aged 6–17 years currently had TS, representing 73% of children ever diagnosed with TS [1]. The prevalence of TS in childhood of 6 per 1000 was replicated in several countries [4–6]. Recent studies also showed that the ratio of males to females with TS aged 4–6 years was approximately 4:1 [7]. In Taiwan, the ratio of male to female was 9–2 and the comorbid rate of ADHD 36%, OCD was 18%, and self-injurious was 27% [8]. The onset of tic symptoms in TS typically occurs during early childhood, and the disorder affects 0.15–3.8% of Western and 0.56% of Taiwanese school-aged children [8– 11]. Children currently with TS are three times as likely as children without TS to have ever had any cooccurring neurobehavioral conditions; 86.5% of children currently with TS had at least one co-occurring neurobehavioral condition [1]. Almost 90% of all children diagnosed with TS exhibit symptoms of one or more comorbid disorders [11]. Among those children with TS, more than half of them show evidence of psychiatric comorbidities, including ADHD, OCD, mood disorders, and behavioral problems [11–13]. Approximately 10% of all children with TS experience mood disorders such as depression [7]. One study found that TS patients were 4.6 times more likely to develop depression than were patients without TS [10]. Similarly, some studies showed that only 12% patients with TS presented with no other coexisting disorders [2,14]. Comorbidity rates associated with TS were 30–50% for ADHD, 25–42% for OCD, and 27% for self-injurious behaviors [15,16]. A recent study also showed that patients with TS have a high risk of developing depression, and males were more likely to be diagnosed with depression than females in Taiwan [11]. In addition, children diagnosed with TS were 2.6-times more likely to have had a brain injury or concussion, and a lower socioeconomic status was also associated with a twofold increase in the risk of TS [1,17]. Instead of removing the tics, the treatment goal for children with TS is maximizing their potential in school settings and social functioning by targeting the following conditions that result from tics [18]: (1) subjective discomfort (e.g., pain or injury); (2) sustained social problems (e.g., social isolation or bullying); (3) social
and emotional problems (e.g., reactive depressive symptoms); and (4) functional interference (e.g., impairment of academic achievements). According to Kurlan [16] clinical guidelines for treating TS and other tic disorders primarily rely on medications, such as alpha agonists (e.g., clonidine and guanfacine), antipsychotics (e.g., haloperidol, fluphenazine, pimozide, and risperidone), and dopamine receptor antagonists (e.g., tetrabenazine). Several trials supported the efficacy of the alpha adrenergic drugs, clonidine and guanfacine, as first-line therapy for TS [16,19]. European clinical guidelines for TS and other tic disorders state that the typical antipsychotics, haloperidol and pimozide, are the most effective medications for tic management [20,21]. Also, a study by Kurlan [16] suggested that the only FDA-approved medications for TS are classical neuroleptic antipsychotic drugs, such as haloperidol and pimozide. These medications work by blocking the production of D2 dopamine receptors antagonist in the brain, which results in suppression of the tics [16]. The most common side effects of these antipsychotic medications are sedation and depression [16]. In addition, alpha agonist medications (e.g., clonidine and guanfacine) are used as firstline therapy for TS and tics, and the effectiveness of treating ADHD children with comorbid TS was evaluated in double-blind, placebo-controlled studies [19,21,22]. In Taiwan, medications commonly used for TS include a2-adrenergic agonists and atypical antipsychotics [23–25]. Effective a2-adrenergic agonists include clonidine. Atypical antipsychotics are the most effective drugs for treating tics because they show reduced incidence of side effects. Examples include aripiprazole, ziprasidone, sulpiride, olanzapine, quetiapine, risperidone, and clozapine. To date, aripiprazole appears to display a novel neuroleptic effect that has been demonstrated to be effective in treating TS children in several studies in Taiwan [23,24,26]. In addition, guanfacine is not used in Taiwan. Recent epidemiologic studies demonstrated that TS is more common than previously recognized. However, previous studies examining the impact of TS have been limited generalizability to larger populations, and behavioral interventions have not been evaluated in large-scale controlled trails. Early treatment of TS involves pharmacologic and/or behavioral interventions [11,16]. Atypical antipsychotics should be the main component of any treatment plan for tics and TS, to aid in treating comorbid disorders such as depression, anxiety, OCD, and ADHD [21]. Nevertheless, relatively little is known about a holistic view of the impacts of tic medication for TS on psychiatric comorbidities while controlling for relevant factors in Taiwan. Also, there is a need for a study with a large sample size and long-term outcomes of medications for TS. The aim of this study was therefore to explore the
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impacts of tic medication on the risk of psychiatric comorbidities among a nationally representative sample of children and adolescents with TS based on the Taiwan National Health Insurance (NHI) Research Database (NHIRD). 2. Methods 2.1. Study design and data source This study uses a retrospective cohort design. Data used for this analysis were from an NHI database. Taiwan implemented its NHI on March 1, 1995, and the health insurance coverage rate currently exceeds 99%. The NHI was launched in Taiwan to provide equal access to adequate health care for all and to provide medicated interventions faster and as needed [27]. The NHI database includes nationwide outpatient/ emergency and hospitalization data, and the law requires that all hospitals and clinics report outpatient/ emergency and hospitalization expenses to the Bureau of NHI on a monthly basis. This study used the Longitudinal Health Insurance Database (LHID), which contains all original claims data of one million beneficiaries, randomly sampled from the registry for Beneficiaries of the NHIRD with more than 23 million individuals enrolled in the NHI program, the universal single-payer for healthcare in Taiwan. The diagnostic codes used in the NHIRD follow the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). Each TS diagnosis was made by a board-certified pediatrician or neurologist according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). The NHI Administration randomly chose the records of 1 in 100 ambulatory care visits and 1 in 20 inpatient claims to verify the accuracy of the diagnoses. Several studies have demonstrated [9] high accuracy and validity of the diagnoses in the NHIRD [27]. Therefore, using the NHIRD is suitable to explore the effects of tic medication on the risk of psychiatric comorbidities in new diagnoses of TS. 2.2. Variable definitions In our research, TS were identified by the ICD-9CM codes of 307.22 and 307.23, which include both outpatient and inpatient participants. Three most common comorbidity event for tracking included ADHD (ICD-9-CM 314), OCD (ICD-9-CM 300.3), and depression (ICD-9-CM 296.20–296.26, 296.30–296.36, 300.4, 311) [10,16]. Medication therapy for TS included alpha-agonists, antipsychotics, and dopamine receptor antagonists [16]. Patients were considered to have low income based on certifications of waived medical copayments.
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2.3. Study sample In Taiwan, TS is diagnosed by health professionals according to DSM-5 to help diagnose tic disorders [28]. To be diagnosed with TS, a person must first have two or more motor tics (for example, blinking or shrugging the shoulders) and at least one vocal tic (for example, humming, clearing the throat, or yelling out a word or phrase), although they might not always happen at the same time. Second, the tics have to have persisted for at least a year. The tics can occur many times a day (usually in bouts) nearly every day, or on and off. Third, the tics must have begun before the age of 18 years. Lastly, the symptoms must not be due to medication or other drugs or to any other medical condition (for example, seizures, Huntington disease, or postviral encephalitis). Individuals aged 6–18 years who had sought medical help from outpatient, emergent, and inpatient departments due to TS were identified as potential subjects for this study. Initially, 935 individuals among 997,213 persons were aged 6–18 years and had been diagnosed with TS from January 1, 2000 to December 31, 2010. The specific inclusion criteria for this study were those newly diagnosed with TS from January 1, 2000 to December 31, 2010. The establishment of the health insurance database began in 1995, but it was not fully guaranteed in the first few years of operation, and the quality of the data in previous years was insufficient. The data improved in 1997, so we purchased the database from 1997 and excluded outpatients or inpatients seen for TS in the period of 1997–1999. We excluded outpatients or inpatients due to TS in 1997–1999 to ensure that the selected cases were new ones in 2000. In addition, new cases of TS who had a past history of ADHD, OCD, or depression in 1997–1999 were also excluded to ensure that the traced comorbidities were not due to the past psychiatric history. Subjects with an unknown gender were also excluded, and the tracking time was 1–11 years. Twelve subjects met the above exclusion criteria. Ultimately, the study sample consisted of 921 individuals; we then divided them into two groups of ‘‘with tic medication therapy (589 individuals)” and ‘‘no tic medication therapy (332 individuals).” Subjects were tracked until December 31, 2010 (Fig. 1). In addition, the patient records were collected from January 1, 2000, to December 31, 2010, and the follow up deadline was until December 31, 2010. After inclusion, the comorbidities of participants with TS were traced. We first included patients with medication and then traced their comorbidities during the follow-up period. The years of follow up between medication groups with and without tics were 3.54 years and 3.06 years, respectively. We calculated the total follow up time until comorbid events for the medication group with tics,
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Fig. 1. Flowchart of study sample selection from the National Health Insurance Research Database in Taiwan. ADHD, attention deficit hyperactivity disorder; OCD, obsessive–compulsive disorder.
which included 589 individuals, from 2000 to 2010. We then determined the mean follow-up time, which was 2.67 years. The same calculation was applied to the medication group without tics, and the follow-up time until comorbid events was 2.11 years.
medication therapy on psychiatric comorbidities. To investigate the interaction effects, we also calculated adjusted HRs stratified by gender and age groups. All statistical analyses were performed with SPSS 22.0 software (SPSS, Chicago, IL, USA), and two-tailed p < 0.05 was considered the threshold for a significant variance.
2.4. Statistical analysis 2.5. Ethical considerations We used Chi-squared/Fisher exact tests and t-tests to compare differences between groups with and without tic medication therapy and from the baseline to the tracking endpoint. A Kaplan-Meier curve and Cox’s proportional hazard regression analysis were performed to calculate the crude and adjusted hazard ratios (HRs), with the 95% confidence interval (CI), for the effect of tic
NHI information offers representative empirical data for medical and health-related research fields. Researchers are required to pass a detailed review by a professional peer review committee before they are allowed to use the Taiwan NHIRD. Because participants’ identities are encrypted in the database, this study did not
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infringe on participants’ right to privacy. Our study had been approved by the hospital IRB committee (Protocol No.16-026-B1). 3. Results 3.1. Characteristics of study subjects As shown in Table 1, the study included a final cohort of 921 participants with Tourette syndrome, comprising 589 patients in the tic medication therapy group and 332 patients in the no tic medication therapy group. The mean age of patients in the tic medication therapy group was younger than in the no tic medication therapy group (9.12 vs. 9.75 years, p < 0.001). Our study revealed that the incidence of TS in Taiwan is about 0.09%, and the prevalence is 0.54%. Regardless of whether TS patients were examined as a group or were divided into different age groups, male patients were more common than female patients. However, this difference did not reach statistical significance. At the end of follow-up, 94 participants in the tic medication therapy group had had a comorbid event, and 90 participants in the no tic medication therapy group had had an event. Compared to the no tic medication therapy group, the medication therapy group had a lower risk of the occurrence of a comorbidity (p < 0.001). Specifically, patients in the medication therapy group had a lower comorbidity proportion of ADHD (p < 0.001), whereas the comorbidity occurrences of OCD and depression did not significantly differ between the tic medication therapy and no tic medication therapy groups (Table 1). There were no significant differences between with and no tic medication therapy groups regarding income, level of care, department visited, brain injury, or number of suicide attempts. The study found that the percentage of comorbidity events during the study period in 2001 was 12.5% through 2008, when it was 23.86%; it then decreased to 17.05% in 2010. Also, the percentage of comorbidity events in males was higher than that in females of 6–18 years of age. 3.2. The effect of tic medication therapy As to the effect of tic medication therapy on psychiatric comorbidities, Cox’s proportional hazard regression analysis showed a statistically significant reduction in ADHD, OCD, and depression in the tic medication therapy group with a crude HR of 0.6 (95% CI = 0.4–0.8, p < 0.001) (Table 2). After controlling for gender, age, income, level of care, department visited, brain injury, and the number of suicide attempts, the risk of psychiatric comorbidities was still significantly lower in the tic medication therapy group (adjusted HR = 0.5, 95% CI = 0.3–0.6, p < 0.001)
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(Table 2). The Kaplan-Meier curve showed a lower risk of psychiatric comorbidities in the tic medication therapy group after controlling for gender, age, income, level of care, department visited, brain injury, and the number of suicide attempts (p = 0.012) (Fig. 2). The event rate of psychiatric comorbidities was 46.60 per 1000 person-years in the tic medication therapy group, and it was 86.90 per 1000 person-years in the no tic medication therapy group. In addition, we conducted an advanced analysis by stratifying by gender and age groups, and results showed a lower risk of event occurrence in the tic medication therapy group in both genders and all age groups after adjusting for income, level of care, department visited, brain injury, and the number of suicide attempts. In other words, regardless of the gender or age group, the effect of tic medication therapy on reducing the risk of psychiatric comorbidities was still significant (Table 3). 4. Discussion The major aim of this study was to explore the impacts of TS medications on the risk of psychiatric comorbidities among a nationally representative sample of children and adolescents with TS using data from the NHIRD in Taiwan. Consistent with a previous study [16], our study found that regardless of TS patients in total or divided into different age groups, male patients were more common than female patients. Compared to the no tic medication therapy group, patients in the medication therapy group had a lower risk of psychiatric comorbidities at the end of follow-up (p < 0.001). Specifically, patients in the medication therapy group had a lower risk of ADHD (p < 0.001), whereas the comorbidities of OCD and depression did not significantly differ between the tic medication therapy and no tic medication therapy groups. After adjusting for gender, age, income, level of care, department visited, brain injury, and the number of suicide attempts, results showed that TS patients with tic medication therapy tended to have fewer occurrences of ADHD, OCD, and depression than those without tic medication therapy (adjusted HR = 0.5, 95% CI = 0.3–0.6, p < 0.001). Further analysis showed that the effect of tic medication therapy was still significant regardless of gender or age group. The most often used medications for TS during the past 10 years included alpha agonists (e.g., clonidine and guanfacine), antipsychotics (e.g., haloperidol, risperidone, fluphenazine, pimozide, aripiprazole, ziprasidone, sulpiride, olanzapine, quetiapine, and clozapine), and dopamine receptor antagonists (e.g., tetrabenazine) [38]. Few studies have examined the effects of medication therapy on improving psychiatric comorbidities. Several trials supported the efficacy of pharmacological therapy (most commonly alpha ago-
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Table 1 Characteristics of the study sample at the baseline. Variable
Total (N = 921) n (%)
Without tic medicine (N = 332) n (%)
With tic medicine (N = 589) n (%)
p
Age, years (mean ± SD)
9.5 ± 2.6
9.8 ± 2.7
9.12 ± 2.3
<0.001
Age groups, years 6–12 years 13–15 years 16–18 years
829 (90.0) 70 (7.6) 22 (2.4)
312 (94.0) 16 (4.8) 4 (1.2)
517 (87.8) 54 (9.2) 18 (3.1)
Gender Male Female
741 (80.5) 180 (19.5)
268 (80.7) 64 (19.3)
473 (80.3) 116 (19.7)
Age group: 6–12 years Male Female
672 (81.1) 157 (18.9)
255 (81.7) 57 (18.3)
417 (80.7) 100 (19.3)
Age group: 13–15 years Male Female
51 (72.9) 19 (27.1)
9 (56.3) 7 (43.8)
42 (77.8) 12 (22.2)
Age group: 16–18 years Male Female
18 (81.8) 4 (18.2)
4 (100) 0 (0)
14 (77.8) 4 (22.2)
Comorbid events With Without
184 (20.0) 737 (80.0)
90 (27.1) 242 (72.9)
94 (16.0) 495 (84.0)
ADHD With Without
156 (16.9) 765 (83.1)
83 (25) 249 (75)
73 (12.4) 516 (87.6)
OCD With Without
15 (1.6) 906 (98.4)
4 (1.2) 328 (98.8)
11 (1.9) 578 (98.1)
Depression With Without
21 (2.3) 900 (97.7)
5 (1.5) 327 (98.5)
16 (2.7) 573 (97.3)
Level of income Low High
16 (1.7) 905 (98.3)
4 (1.2) 328 (98.8)
12 (2.0) 577 (98.0)
Level of care Medical hospital Regional hospital Local hospital Physician clinic
150 (16.7) 137 (15.2) 22 (2.4) 592 (65.7)
43 (13.0) 46 (13.9) 17 (5.1) 226 (68.1)
107 (18.8) 91 (16.0) 5 (0.9) 366 (64.3)
Department visited Pediatrics Psychiatry Others
607 (65.9) 206 (22.4) 108 (11.7)
218 (65.7) 75 (22.6) 39 (11.8)
389 (66.0) 131 (22.2) 69 (11.7)
Brain Injury With Without
0 (0) 921 (100)
0 (0) 332 (100)
0 (0) 589 (100)
No. of suicide attempts 0 1
921 (100) 0 (0)
332 (100) 0 (0)
589 (100) 0 (0)
0.475
0.387
0.086
0.418
<0.001
<0.001
0.319
0.171
0.258
0.143
0.992
–
–
nists and antipsychotics) for TS. Alpha-2 adrenergic drugs, including clonidine and guanfacine, are also efficacious for ADHD [19,20]. Indeed, alpha agonists may be a good first-line treatment in patients with both tics
and ADHD [16]. Atypical antipsychotics should be an option for tics and TS to aid in treating comorbid disorders such as depression, anxiety, OCD, and ADHD [2,3,19].
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379
Table 2 Factors of comorbid events (attention deficit hyperactivity disorder/obsessive–compulsive disorder/depression) at the end of follow-up using a Cox regression. Variable
Crude HR (95% CI)
p
Adjusted HR (95% CI)
p
Tic medicine therapy With Without
0.6 (0.4–0.8) Reference
<0.001
0.5 (0.3–0.6) Reference
<0.001
Gender Male Female
2.1 (1.3–3.3) Reference
<0.001
1.2 (0.7–2.0) Reference
0.469
Starting age group (years) 6–12 13–15 16–18
Reference 1.6 (1.0–2.6) 2.0 (1.0–4.1)
Level of income Low High
0.7 (0.2–2.6) Reference
0.54
0.3 (0.1–1.3) Reference
0.10
Level of care Medical hospital Regional hospital Local hospital Physician clinics
17.1 (11.02–26.42) 14.0 (9.0–21.9) 8.3 (4.2–16.4) Reference
<0.001 <0.001 <0.001
15.3 (9.7–24.0) 11.3 (7.1–17.9) 8.7 (4.4–17.2) Reference
<0.001 <0.001 <0.001
Department visited Pediatrics Psychiatry Others
0.72 (0.1–5.1) 5.73 (4.3–7.7) Reference
0.74 <0.001
1.3 (0.2–9.5) 3.36 (2.5–4.6) Reference
0.79 <0.001
0.048 0.052
Reference 1.3 (0.8–2.1) 1.2 (0.6–2.5)
0.258 0.619
HR, hazard ratio; CI, confidence interval.
Fig. 2. Kaplan-Meier curve for cumulative survive of events (attention deficit hyperactivity disorder (ADHD)/obsessive–compulsive disorder (OCD)/depression) stratified by tic medicine therapy according to the log-rank test.
However, atypical antipsychotics are often associated with adverse effects [21]. It was recommended that OCD is genetically associated with TS [2,3,19]. OCD symptoms are significantly related to core symptoms of TS [23]. One study also found that patients with TS
reported similar scores as those patients with major depressive disorder on obsessionality, indicating that obsessionality commonly occurs in TS [30]. TS comorbid with OCD is associated with more-severe tics, echophenomena, ADHD, and depression [31]. The effec-
380
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Table 3 Factors of comorbid events (attention deficit hyperactivity disorder/obsessive–compulsive disorder/depression) at the end of follow-up stratified by gender and age group using a Cox regression. py
With tic medicine (N = 589)
Without tic medicine (N = 332) (Reference)
Adjusted HR (95% CI)
p
86.9
0.458 (0.3–0.6)
<0.001
799 236.68
103.9 29.6
0.43 (0.3–0.6) 0.6 (0.2–0.8)
<0.001 <0.01
978.3 50.97 6.38
84.8 78.5 470.2
0.4 (0.3–0.6) 0.7 (0.1–0.8) 0.4 (0.1–0.7)
<0.001 <0.01 <0.01
Comorbid events
PYs
Rate (per 103)
Comorbid events
PYs
Rate (per 103)
Total
94
2017.29
46.6
90
1035.7
Gender Male Female
81 13
1527.06 490.23
53 26.5
83 7
1697.66 287.8 31.83
43 55.6 157.1
83 4 3
Age group (years) 6–12 73 13–15 16 16–18 5
PYs, person-years; HR, hazard ratio; CI, confidence interval.
tiveness of medication therapy in improving psychiatric comorbidities may be explained by a common neuropsychiatric mechanism among TS, ADHD, OCD, and depression. For example, it was recommended that because of complicated interactions between dopamine and serotonin in the brain, it is possible that both systems play a role in both TS and OCD, suggesting that medications which are effective in OCD (such as serotonin reuptake inhibitors (SRIs), may also be useful for treating TS [32]. In Taiwan, two classes of medicine are widely used for TS: a2-adrenergic agonists and atypical antipsychotics [23,25]. Clonidine is usually the first-line medication for previously untreated TS patients. Aripiprazole appears to display a novel neuroleptic effect that has been demonstrated to be effective in treating TS children in several studies [23,25,26]. In 2016, the Ministry of Health and Welfare also approved the use of aripiprazole to treat dysentery, and it is also the first choice in Taiwan [24,25]. TS has been shown to have a prevalence of about 6 per 1000 among childhood in several countries [4–6]. The onset of tic symptoms in TS typically occurs during early childhood, and the disorder affects 0.15–3.8% of children in Western countries [9]. Wang did an epidemiological study in an elementary school with 2000 Taiwanese children with TS, which had a prevalence of about 0.56% [8]. Our study also found a similar prevalence of TS for children aged 6 to 18 years of around 0.54%. However, the prevalence in Taiwan is lower than in Western countries. This might be due to the insufficient awareness about TS in Taiwan, where many pediatric patients do not receive early diagnosis and are mistreated or punished because of their disorderrelated behaviors. Our study found that the percentage of comorbidity events during the study period was lower than in other studies. For example, one Canadian study examined 65 individuals with TS identified in childhood and 65 matched community controls without tics or OCD symptoms. The participants were assessed around
18 years of age in regard to psychosocial functioning and lifetime psychiatric disorders. It was found that approximately 40% of children with TS had experienced depression or OCD [33]. In a Swedish study of 4479 school-aged children, 25 had TS, 34 had chronic motor tics (CMT), 24 had chronic vocal tics (CVT), and 214 had transient tics (TT) during the past year. A three-stage procedure was used, which involved tic screening, telephone interviews, and clinical assessment. The TS group was compared with 25 children with TT and 25 controls without tics. The study found that 66% of the TS cases had comorbid ADHD, and 54% of the children with TS had comorbid OCD [34]. The inconsistency with our findings might be because our study used existing diagnoses that were available in a dataset without clinical assessment or diagnosis tools like those used in other studies to confirm the diagnosis, which might have resulted in underestimation of the occurrence of psychiatric comorbidities. In line with previous studies, our study found that ADHD was the most common comorbid disorder. Previous studies found that rates of ADHD comorbidity were 38% and 60% in community and referral centers, respectively. ADHD usually occurs approximately 2– 3 years before tics, and a smaller proportion of ADHD patients are found only after tics [35]. Studies suggested that patients with TS and ADHD demonstrated more maladaptive behaviors and showed negative impacts on psychosocial outcomes [29]. Regardless of clinical or community populations, approximately 90% of patients with TS had comorbidities of other psychiatric diagnoses [36]. One study in Japan found that TS patients with comorbidities of OCS and/or hyperkinetic disorder (HD) demonstrated significantly more coprophenomena, higher prevalence rates of impulsiveness/aggression (48.8% vs. 8.3%), school refusal (34.1% vs. 14.3%), self-injurious behaviors (19.0% vs. 2.8%), and clumsiness (23.3% vs. 2.9%) than did the TS-only group [37]. Compared to the TS only or control group, youngsters with TS and ADHD
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showed more internalized behavioral problems and poorer social adaptation [36]. Therefore, it is suggested that all pediatric patients with tics should be screened for an ADHD diagnosis when seeking medical attention [38] and this apparently implies that further management and prognoses may be required [36]. We found that among a final cohort of 921 participants with TS, 332 (36.05%) patients were in the no tic medication therapy group. Treatment of tics needs to be individually tailored, especially when other comorbid disorders occur and affect the clinical course [39]. It is recommended that pharmacological treatment is not always required. Situations can be used to judge which medications have the most troublesome signs (motor component, urge, ADHD, OCD), and interfere with daily living, school, and social functioning [40]. Indeed, it is laborious to provide guidelines about indications for the pharmacological treatment of TS. First, a high interindividual variability of symptoms is shown in patients with TS. Furthermore, there are temporal variations in tics, and the treatment effects for the tics may be affected by coexisting conditions. Furthermore, subjective impairment and objective tic severity are not necessarily correlated with each other. In some cases, people with severe tics show mild impairment, whereas in other cases, mild tics may be associated with significant suffering [18,41]. Although our study found that TS medication was effective in improving the risk of psychiatric comorbidities, the treatment of TS still needs to involve appropriate psychoeducation, behavioral interventions (such as a comprehensive behavioral intervention for tics (CBIT), and social support [16]. In addition to individual considerations for pharmacological treatment, TS medications are often associated with adverse effects, which further result in patients discontinuing their medication. One study [42] reported that 66.7% of patients had discontinued haloperidol due to its intolerable side effects. Although aripiprazole is considered to have fewer adverse effects compared to other atypical antipsychotics, one study still found that 20.7% of patients discontinued its use because of the severity of side effects such as sedation and sleep problems [43]. In Taiwan, caregivers of patients with TS might be concerned about the side effects of medication and refuse to accept pharmacological treatment for those patients. On the other hand, TS patients might also refuse to continue to take a medication because of interruptions to school life due to intolerable adverse drug reactions. 5. Limitations This study has three limitations. First, this study excluded people who were older than 18 years, those who were healthy and did not have health insurance,
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and those who were not covered by NHI program in Taiwan. Second, this study may have been vulnerable to a possible urban–rural imbalance in awareness of mental disorders and access to clinical services. Finally, this study used a claims dataset with scrambled patient identification in order to protect patient’s privacy; therefore, it lacked detailed patient information, such as symptom severity, physical activity of patients, socioeconomic status, and family history of systemic or neuropsychiatric diseases, which may be potential risk factors and confounders related to psychiatric comorbidities. Even though Taiwan’s NHI administration randomly examines cases in order to ensure the accuracy of its database, evidence from a cohort study is usually less reliable than random trials, since a cohort study design is subjected to many biases related to confounder adjustments. We suggest that a future study should be conducted using both qualitative interviews and questionnaire surveys to compare results obtained in this study. 6. Conclusions The studies of TS have been very limited in Taiwan, in particular, relationships between tic medication therapy and psychiatric comorbidities of children and adolescents remain unclear. This study provides the first nationwide, population-based study of children and adolescents with TS in Taiwan which explored the impacts of TS medication on the risk of psychiatric comorbidities. Results revealed that the risk of the occurrence of comorbidities was significantly lower in the tic medication therapy group and also provide evidence to inform the prognoses of patients with TS. These findings imply the importance of early identification and pharmacological treatment which might be helpful in decreasing psychiatric comorbidities. Further studies are still needed to compare and explore the effects of pharmacological and psychosocial treatments.
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